8-95048547-CAC-TAT

Variant names:

• chr8-95048547-CAC-TAT
• NM_152416.4:c.805_807delCACinsTAT
• NDUFAF6 p.His269Tyr

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5 PP3

The NM_152416.4(NDUFAF6):​c.805_807delCACinsTAT​(p.His269Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H269D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFAF6 NM_152416.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.56
• Publications: 0 publications found

Genes affected

NDUFAF6 (HGNC:28625): (NADH:ubiquinone oxidoreductase complex assembly factor 6) This gene encodes a protein that localizes to mitochondria and contains a predicted phytoene synthase domain. The encoded protein plays an important role in the assembly of complex I (NADH-ubiquinone oxidoreductase) of the mitochondrial respiratory chain through regulation of subunit ND1 biogenesis. Mutations in this gene are associated with complex I enzymatic deficiency. [provided by RefSeq, Nov 2011]

NDUFAF6 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency, nuclear type 17

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• primary Fanconi syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi renotubular syndrome 5

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-95048547-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 372255.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152416.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF6	NM_152416.4	MANE Select	c.805_807delCACinsTAT	p.His269Tyr	missense	N/A	NP_689629.2	Q330K2-1
	NDUFAF6	NM_001354516.2		c.649_651delCACinsTAT	p.His217Tyr	missense	N/A	NP_001341445.1	Q330K2-2
	NDUFAF6	NM_001330582.2		c.529_531delCACinsTAT	p.His177Tyr	missense	N/A	NP_001317511.1	A0A075B6P0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF6	ENST00000396124.9	TSL:2 MANE Select	c.805_807delCACinsTAT	p.His269Tyr	missense	N/A	ENSP00000379430.4	Q330K2-1
	NDUFAF6	ENST00000875013.1		c.784_786delCACinsTAT	p.His262Tyr	missense	N/A	ENSP00000545072.1
	NDUFAF6	ENST00000940120.1		c.805_807delCACinsTAT	p.His269Tyr	missense	N/A	ENSP00000610179.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-96060775;